ARTful ageing: epigenetic rejuvenation in people with HIV
Authors: Boghuma K Titanji
Journal: The Lancet Healthy Longevity (2023)

The global epidemic of HIV has been ongoing for over 40 years, and during this time, antiretroviral therapy (ART) has been the most transformative intervention for improving the life-expectancy and overall health of people living with HIV. Despite considerable advances in HIV treatment, including daily, single-pill options and long-lasting, injectable ART formulations, people living with HIV continue to experience accelerated ageing and non-AIDS-related chronic comorbidities, which disproportionately affect their health and wellbeing.1Deeks SG Lewin SR Havlir DV The end of AIDS: HIV infection as a chronic disease.Lancet. 2013; 382: 1525-1533Summary Full Text Full Text PDF PubMed Scopus (1200) Google Scholar About 37 million people worldwide are living with HIV, and although 75% of these people are receiving ART, a lifelong commitment to treatment is necessary to maintain control of the infection and sustain suppression of viral replication in the absence of a definitive cure. Comprehensive care for people living with HIV requires a better understanding of the long-term consequences of living with the virus, the impact of ART on ageing with HIV, and interventions to address non-AIDS-related chronic comorbidities. The study by Isabella C Schoepf and colleagues,2Schoepf IC Esteban-Cantos A Thorball CW et al.Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 years.Lancet Healthy Longev. 2023; 4: e211-e218Summary Full Text Full Text PDF Scopus (1) Google Scholar published in this issue of The Lancet Healthy Longevity, offers important insight into the relationship between HIV, ART, and biological ageing. The findings reveal that untreated HIV infection over a long period is associated with significant acceleration in epigenetic ageing. With individuals in this study serving as their own controls, initiation of ART led to a significant reversal in five established measures of epigenetic ageing and more closely mirrored the epigenetic age that would be anticipated for a patient's chronological age. Epigenetic approaches have been used to examine accelerated ageing in people living with HIV and several studies have shown that epigenetic age acceleration occurs in people living with HIV compared with healthy controls.3Titanji BK Gwinn M Marconi VC Sun YV Epigenome-wide epidemiologic studies of human immunodeficiency virus infection, treatment, and disease progression.Clin Epigenetics. 2022; 14: 8Crossref PubMed Scopus (5) Google Scholar, 4Esteban-Cantos A Rodríguez-Centeno J Barruz P et al.Epigenetic age acceleration changes 2 years after antiretroviral therapy initiation in adults with HIV: a substudy of the NEAT001/ANRS143 randomised trial.Lancet HIV. 2021; 8: e197-e205Summary Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 5Horvath S Levine AJ HIV-1 infection accelerates age according to the epigenetic clock.J Infect Dis. 2015; 212: 1563-1573Crossref PubMed Scopus (346) Google Scholar An older epigenetic age can be considered a surrogate marker of accelerated biological ageing relative to an individual's chronologic age, and could have implications for changes in gene expression underlying the decline in physiological function that occurs with age.6Levine ME Lu AT Quach A et al.An epigenetic biomarker of aging for lifespan and healthspan.Aging (Albany NY). 2018; 10: 573-591Crossref PubMed Scopus (897) Google Scholar These findings align with other longitudinal cohorts which have shown that epigenetic age acceleration in people living with HIV begins at initial HIV infection.7Breen EC Sehl ME Shih R et al.Accelerated aging with HIV begins at the time of initial HIV infection.iScience. 2022; 25104488 Summary Full Text Full Text PDF Scopus (4) Google Scholar It is important to explore, using larger cohorts, how ART-induced epigenetic rejuvenation affects the progression or development of ageing-related comorbidities such as cardiovascular diseases, cancer, and neurocognitive decline in people living with HIV. The proposition that ART could serve as a drug intervention for ageing reversal in people living with HIV also has implications for therapeutic approaches for reversing biological ageing in the broader population and could help unravel important pathophysiological mechanisms underlying this phenomenon. The effects of different classes of antiretroviral drugs on the process of epigenetic ageing reversal need to be clarified in future studies. Protease inhibitors are associated with increased risk for metabolic diseases that could have an impact on biological ageing, such as dyslipidemia and insulin resistance,8Rao MN Lee GA Grunfeld C Metabolic abnormalities associated with the use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors.Am J Infect Dis. 2006; 2: 159-166Crossref PubMed Google Scholar and some integrase inhibitors are associated with increased risk of weight gain.9Eckard AR McComsey GA Weight gain and integrase inhibitors.Curr Opin Infect Dis. 2020; 33: 10-19Crossref PubMed Scopus (87) Google Scholar It is yet to be determined whether different classes of antiretroviral drugs will have differential benefits on epigenetic ageing reversal and whether this will become an important consideration for ART strategies in the future. Late presentation of HIV remains a substantial issue in clinical practice, with almost 50% of patients in the examined cohort initiating ART only after several years of living with HIV. WHO guidelines recommend initiating ART as soon as possible following an HIV diagnosis. However, one in four adults with HIV globally are not receiving ART, and only half of the children with HIV in Africa are receiving treatment.10UNAIDSIn danger: UNAIDS Global AIDS Update 2022. UNAIDS, Geneva2022Crossref Google Scholar Epigenetic age acceleration was shown to be associated with worse health outcomes in people living with HIV and increased mortality risk was observed in one study of over 500 participants.11Oursler KK Marconi VC Wang Z et al.Epigenetic age acceleration markers are associated with physiologic frailty and all-cause mortality in people with Human Immunodeficiency Virus.Clin Infect Dis. 2023; 76: e638-e644Crossref Scopus (4) Google Scholar These findings underscore the importance of early initiation of ART and the need to ensure equitable access to treatment for people living with HIV worldwide. It is important to note that findings of the study by Schoepf and colleagues might not be fully generalisable to other racial groups or paediatric cohorts as it predominantly included White adults with HIV. Future studies of more diverse cohorts are needed to confirm these effects in other groups. In conclusion, there is still much to be learned about ageing with HIV, including the underlying mechanisms that drive accelerated epigenetic ageing and the effectiveness of interventions to slow or reverse these changes. Addressing the implications of epigenetic ageing in HIV is crucial to improving the health and wellbeing of people living with this virus. ART remains the most important weapon in our arsenal and could also be key to slowing down the inevitable process of ageing. I receive grant support from the Building Interdisciplinary Careers in Women's Health (BIRCWH) and from Emory Center for AIDS Research (P30AI050409). I have received honoraria for consulting work not related to the topic of the current manuscript from the non-profit CRITICA and from ISMIE, GSK and Harvard University for lectures on topics unrelated to this work. Epigenetic ageing accelerates before antiretroviral therapy and decelerates after viral suppression in people with HIV in Switzerland: a longitudinal study over 17 yearsIn a longitudinal study over more than 17 years, epigenetic ageing accelerated during untreated HIV infection and decelerated during suppressive ART, highlighting the importance of limiting the duration of untreated HIV infection. Full-Text PDF Open Access